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Design, Synthesis, and Biological Evaluation of Artemisinin‐Piperazine‐Phosphoramide Mustard Hybrids as Potential Anticancer Agents

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Twelve novel artemisinin-piperazine-phosphoramide mustard (PPM) hybrids 7 al were synthesized via an efficient, catalyst-free two-step sequential substitution. Artemisinin-PPM hybrids 7 showed better cytotoxicity than DHA and VCR. Cytotoxicity was significantly enhanced by the introduction of a thiazole moiety. Hybrid 7 h displayed 7.4-fold stronger potency than VCR, and is both the most potent compound synthesised, and the most selective (selectivity index=16).


Abstract

A series of novel artemisinin-piperazine-phosphoramide mustard (PPM) hybrids were designed and synthesized by incorporating phosphoramide mustard (PM) into dihydroartemisinin (DHA) via an efficient, catalyst-free two-step sequential substitution. Artemisinin-PPM hybrids showed better cytotoxic potency against HepG2 cells than both the parent DHA and the reference, vincristine (VCR). Structure-activity relationship (SAR) studies showed that the cytotoxicity was significantly enhanced by the introduction of a thiazole moiety. Hybrid 7 h, the most potent compound with the highest selectivity index IC50 (HEK-293T)/IC50 (HepG2)=16, displayed 7.4-fold stronger potency than VCR against HepG2 cells. In addition, hybrid 7 h was substantially more cytotoxic on all human cancer cells tested than on the corresponding non-cancerous cells. Flow cytometric analysis showed that 7 h significantly blocked the cell cycle in the G0/G1 phase and induced apoptosis in a concentration-dependent manner.

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